CN104693186B - C F keys generation C N are bonded to the method that class medicine is dissolved in west in a kind of indole derivatives - Google Patents
C F keys generation C N are bonded to the method that class medicine is dissolved in west in a kind of indole derivatives Download PDFInfo
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- CN104693186B CN104693186B CN201410850638.4A CN201410850638A CN104693186B CN 104693186 B CN104693186 B CN 104693186B CN 201410850638 A CN201410850638 A CN 201410850638A CN 104693186 B CN104693186 B CN 104693186B
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Abstract
The invention belongs to organic synthesis field, C F keys generation C N are bonded to the method that class medicine is dissolved in west in specifically a kind of indole derivatives.Using six/heptatomic ring lactim D as reaction substrate, in presence of organic solvent, class medicine F is dissolved containing indole ring west by what Cu catalyst actions and N Boc piperazines E generated yield >=90%, is CuCl according to the upper Cu catalyst, one or more in CuBr, CuI.The fracture of C F keys is carried out under strong basicity environment in synthetic method of the present invention, catalyst is used as using more cheap Cu, not only reduce the difficulty of cost and post-reaction treatment, the transition metal-catalyzed application value in pharmaceutical synthesis can more be embodied, present invention reaction is simpler easy to operate, and reaction is gentle, and the time is moderate, yield is high, is had laid a good foundation for the industrialized production of next step.
Description
Technical field
The invention belongs to organic synthesis field, C-F keys generation C-N is bonded to west in specifically a kind of indole derivatives
Dissolve the method for class medicine.
Background technology
Indole derivatives is widely present in nature, is primarily present in natural flower oil, as Jasmine, bigarabe flower, daffodil,
In fragrant rowland etc., be it is a kind of with the closely bound up medicine of human life activity, such as：Maintain human body spirit and activity of having a normal thinking
Serotonin (serotonin) and the indigo red (indirubin) acted on obvious anticancer, central nervous system stimulant
Harmine (Harmine) etc..
Before 19th century, it is a kind of important dyestuff that research of the people for indoles, which also only rests on it, but with section
Development, and people being continually striving to and exploring, and arrived in the 1930s, the research of Benzazole compounds is to one
New stage, it has been appeared in many alkaloids by as a core group, has been pulled open the sequence of indole derivatives research since then
Curtain, even to this day, the research of indole derivatives is still a very active research topic.Secondly, heterocyclic drug is synthesis
The most major class medicine of proportion in medicine, there are a hexa-member heterocycle or a seven membered heterocyclic respectively in this construction unit,
Class medicine is dissolved in macromolecular west containing six, seven membered heterocyclic mostly has very high pharmaceutical properties, such as：Calm, hypnosis and antianxiety
Deng, new pyridine and sulphur nitrogen heptatomic ring derivative with extensive antitumor activity, anti-tubercular drug, rifampicin, strepto-
Element, spirituality medicine carbamazepine and Clozapine etc..In view of the above, class medicine is dissolved in the west containing hexa-member heterocycle or seven membered heterocyclic
Thing, it will be a very important drug molecule, so as to expand the research contents of medicine.
The content of the invention
Present invention aims at provide C-F keys generation C-N in a kind of indole derivatives to be bonded to the western method for dissolving class medicine.
To achieve the above object, the present invention use technical scheme for：
C-F keys generation C-N is bonded to the method that class medicine is dissolved in west in a kind of indole derivatives, and reaction equation is as follows,
R1For indoles, 5- chloro-indoles, 5- methyl indols, furans or 5- methylfurans.
R2For aryl rings, alkyl ring, five heterocycles, six heterocycles or seven heterocycles.
N is 6 or 7.
Using six/heptatomic ring lactim D as reaction substrate, in presence of organic solvent, by Cu catalyst actions with
N-Boc- piperazines E generation yield >=90% dissolves class medicine F containing indole ring west.
The Cu catalyst is CuCl, the one or more in CuBr, CuI, preferably CuBr.
Wherein, the volume and mass ratio of organic solvent and compound intermediate D are 10: 1~15: 1, it is preferable that volume mass
Than for 12: 1.
Cu catalyst is 0.2~0.4: 1 with compound intermediate D mol ratios, preferred molar ratio 0.2: 1.
N-Boc- piperazines E and compound intermediate D mol ratio is 0.9~1.1: 1, preferred molar ratio 1: 1.
The organic solvent is acetonitrile, tetrahydrofuran, dioxane, the one or more in dichloromethane, is preferably
THF。
Product filtering, concentration, washing, extraction, concentration and crystallization after the reaction, that is, obtain yield >=90% contains Yin
Dissolve class medicine F in diindyl ring west.
Product filters after the reaction, is concentrated into condenser pipe almost no liquid and drips, rear water-soluble with 10% sodium carbonate
Liquid washs, then is extracted by ethyl acetate, after organic phase filtering dried over sodium sulfate, then it is concentrated to almost not having in condenser pipe
Liquid drips, after dissolved with methanol, methyl tertiary butyl ether(MTBE) crystallization, that is, obtain yield >=90% dissolves class medicine containing indole ring west
F。
Advantage for present invention：The fracture of C-F keys is carried out under strong basicity environment in reaction system of the present invention,
Using more cheap Cu as catalyst, the difficulty of cost and post-reaction treatment is not only reduced, can more embody transition
Application value of the metal catalytic in pharmaceutical synthesis, present invention reaction is simpler easy to operate, and reaction is gentle, and the time is moderate, production
Rate is high, is had laid a good foundation for the industrialized production of next step.
Brief description of the drawings
Fig. 1 is that product F 6 provided in an embodiment of the present invention takes off the nuclear magnetic data figure after Boc.
Specific implementation method
Technical scheme is described in further detail with reference to embodiment, in following embodiments
Solvent for use or reagent are pure to analyze；Following examples are intended to illustrate invention, are not intended to limit the present invention.
Embodiment 1
Class medicine F1 synthesis is dissolved containing indole ring west
Reaction equation is：
Wherein, in heptatomic ring lactim D：Ri=indole ring, R2=phenyl ring.
In 500mL flasks, add heptatomic ring lactim D1 20g and N-Boc- piperazine E 12.66g and add 240mL
Tetrahydrofuran, Cu catalyst (referring to table 1) is then added, at 25 DEG C of normal temperature, react 10 hours, after filtering, be evaporated under reduced pressure to cold
Almost no liquid drips in solidifying pipe.100mL ethyl acetate and 50mL sodium carbonate liquors (10%) are added in grease, point
Liquid, organic phase 100mL water washings, is filtered after washing through anhydrous sodium sulfate drying, is evaporated under reduced pressure to almost not having in dry condenser pipe
There is liquid to drip, add the dissolving of 20mL methanol, use 100mL methyl tertiary butyl ether(MTBE) crystallizations afterwards, that is, obtain shown in red formula one
Class medicine F1 is dissolved containing indole ring west.
Table 1
| Cu catalyst | Cu catalyst charges | Target compound synthetic quantity | The yield of synthesising target compound | |
| 1 | CuBr | 5.8g | 28.74g | 92.08% |
| 2 | CuCl | 4.0g | 23.43g | 75.06% |
| 3 | CuI | 7.8g | 28.74g | 92.08% |
Embodiment 2
Class medicine F1 synthesis is dissolved containing indole ring west
In 500mL flasks, respectively by heptatomic ring lactim D1 (wherein, R1=indole ring, R2=phenyl ring) 20g, N-
Boc- piperazine E 12.66g and CuBr 5.8g are added in reaction bulb, in presence of organic solvent (referring to table 2), normal temperature 25
At DEG C, react 10 hours, after filtering, be evaporated under reduced pressure to almost no liquid drips in condenser pipe.100mL is added in grease
Ethyl acetate and 50mL sodium carbonate liquors (10%), liquid separation, organic phase 100mL water washings, do after washing through anhydrous sodium sulfate
It is dry.Almost no liquid drips in vacuum distillation to condenser pipe, then adds the dissolving of 20mL methanol, uses 100mL methyl- tert fourths afterwards
Base ether crystallization, that is, obtain and dissolve class medicine F1 containing indole ring west shown in red formula one.
Table 2
| Organic solvent | Organic solvent addition | Target compound synthetic quantity | The yield of synthesising target compound | |
| 1 | THF | 240mL | 28.88g | 92.52% |
| 2 | Acetonitrile | 240mL | 26.69g | 85.53% |
| 3 | Dichloromethane | 240mL | 18.73g | 60.00% |
| 4 | Dioxane | 240mL | 27.17g | 87.05% |
Embodiment 3
Class medicine F1 synthesis is dissolved containing indole ring west
In 150mL flasks, heptatomic ring lactim D1 (wherein, R are added1=indole ring, R2=phenyl ring) 10g, N-Boc-
Piperazine E 6.33g and CuBr 2.9g are added in reaction bulb, add 80mL tetrahydrofurans, and at 25 DEG C of normal temperature, reaction 10 is small
When, after filtering, it is evaporated under reduced pressure to almost no liquid drips in condenser pipe.50mL ethyl acetate and 30mL are added in grease
Sodium carbonate liquor (10%), liquid separation, organic phase 50mL water washings, through anhydrous sodium sulfate drying after washing.It is evaporated under reduced pressure to cold
Almost no liquid drips in solidifying pipe, then adds the dissolving of 10mL methanol, uses 50mL methyl tertiary butyl ether(MTBE) crystallizations afterwards, that is, obtain red
Shown in color formula one class medicine F1 is dissolved containing indole ring west：12.57g, yield 80.50%.
Embodiment 4
Class medicine F2 synthesis is dissolved containing indole ring west
Reaction equation is as follows：
Wherein, in heptatomic ring lactim D2：R1=5- chloro-indole rings, R2=3- methoxyl group phenyl ring.
In 500mL flasks, heptatomic ring lactim D2 30g, N-Boc- piperazine E 15.54g and CuBr 2.37g are added
It is added in reaction bulb, adds 360mL tetrahydrofurans, at 25 DEG C of normal temperature, reacts 10 hours, after filtering, be evaporated under reduced pressure to cold
Almost no liquid drips in solidifying pipe.150mL ethyl acetate and 75mL sodium carbonate liquors (10%) are added in grease, point
Liquid, organic phase 150mL water washings, through anhydrous sodium sulfate drying after washing.Almost there is no liquid in vacuum distillation to condenser pipe
Drip, then add the dissolving of 30mL methanol, use 150mL methyl tertiary butyl ether(MTBE) crystallizations afterwards, that is, obtain containing shown in red formula two
Dissolve class medicine F2 in indole ring west：40.24g, yield 92.06%.
Embodiment 5
Class medicine F3 synthesis is dissolved containing indole ring west
Synthetic reaction formula is as follows：
Wherein, in heptatomic ring lactim D3：R1=indole ring, R2=3- methoxyl group phenyl ring.
In 1500mL flasks, heptatomic ring lactim D3 80g, N-Boc- piperazine E 45.77g and CuBr are added
6.98g is added in reaction bulb, adds 960mL tetrahydrofurans, at 25 DEG C of normal temperature, is reacted 10 hours, after filtering, is evaporated under reduced pressure
Almost no liquid drips in condenser pipe.400mL ethyl acetate and 200mL sodium carbonate liquors are added in grease
(10%), liquid separation, organic phase 400mL water washings, through anhydrous sodium sulfate drying after washing.In vacuum distillation to condenser pipe almost
There is no liquid to drip, then add the dissolving of 80mL methanol, use 400mL methyl tertiary butyl ether(MTBE) crystallizations afterwards, that is, obtain the red institute of formula three
That shows dissolves class medicine F3 containing indole ring west：111.16g yield 92.34%.
Embodiment 6
Class medicine F6 synthesis is dissolved containing indole ring west
Synthetic reaction formula is as follows：
Wherein, in hexatomic ring lactim D6：R1=indole ring, R2=phenyl ring.
In 1000mL flasks, heptatomic ring lactim D6 40g, N-Boc- piperazine E 26.77g and CuBr are added
4.08g is added in reaction bulb, adds 480mL tetrahydrofurans, at 25 DEG C of normal temperature, is reacted 10 hours, after filtering, is evaporated under reduced pressure
Almost no liquid drips in condenser pipe.200mL ethyl acetate and 100mL sodium carbonate liquors are added in grease
(10%), liquid separation, organic phase 200mL water washings, through anhydrous sodium sulfate drying after washing.In vacuum distillation to condenser pipe almost
There is no liquid to drip, then add the dissolving of 40mL methanol, use 200mL methyl tertiary butyl ether(MTBE) crystallizations afterwards, that is, obtain the red institute of formula four
That shows dissolves class medicine F6 containing indole ring west：58.43g, yield 91.34%.Product F 6 takes off the nuclear magnetic data after Boc：d-
HNMR (500Hz), 7.97-7.95 (1H, m), 7.62-7.50 (5H, m), 7.41-7.38 (1H, m), 7.31-7.26 (1H, m),
7.16-7.11 (1H, m), 3.09 (4H, t, J=36Hz), 2.68 (4H, t, J=55Hz) (referring to Fig. 1).
It is described above, it is only the representative example of the present invention, any formal limitation not is done to the present invention；To the greatest extent
The present invention is described in detail with reference to the foregoing embodiments for pipe, for the person of ordinary skill of the art, still may be used
To be modified to the technical scheme described in previous embodiment, or equivalent substitution is carried out to which part technical characteristic；And
These modifications or equivalent substitution, belong to protection scope of the present invention.
Claims (1)
1. C-F keys generation C-N is bonded to the method that class medicine is dissolved in west in a kind of indole derivatives, it is characterised in that：Reaction equation is such as
Under,
R1 is indoles, 5- chloro-indoles；
R2 is phenyl ring, 3- methoxyl group phenyl ring；
N is 6 or 7；
Using six/heptatomic ring lactim D as reaction substrate, in the presence of THF, by Cu catalyst actions and N-Boc- piperazine E,
Reacted 8~12 hours under 20 DEG C~25 DEG C, normal pressure, generation yield >=90% dissolves class medicine F containing indole ring west；
Wherein, THF and compound intermediate D volume and mass ratio are 10:1~15:1；
Cu catalyst is 0.2~0.4 with compound intermediate D mol ratios：1；
N-Boc- piperazines E and lactim D mol ratio is 0.9~1.1：1；
The Cu catalyst is CuBr；
Product filters after the reaction, is concentrated after filtering, then is washed with 10% aqueous sodium carbonate, then extracts by ethyl acetate
Take, after organic phase filtering dried over sodium sulfate, then it is concentrated, the dissolving of concentrate again with methanol, methyl tertiary butyl ether(MTBE) crystallization, produce
To yield >=90% class medicine F is dissolved containing indole ring west.
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| CN108864089A (en) * | 2018-08-01 | 2018-11-23 | 河南湾流生物科技有限公司 | A kind of new indole and pyridone drug molecule and its preparation method and application |
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| AU2004213374A1 (en) * | 2003-02-14 | 2004-09-02 | Wyeth | Heterocyclyl-3-sulfonylindazoles as 5-hydroxytryptamine-6 ligands |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108864089A (en) * | 2018-08-01 | 2018-11-23 | 河南湾流生物科技有限公司 | A kind of new indole and pyridone drug molecule and its preparation method and application |
| CN108864089B (en) * | 2018-08-01 | 2020-01-10 | 日照巴洛特药业有限公司 | Indolopyridone drug molecule and preparation method and application thereof |
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